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Importance of Racemates and Active Metabolites in Understanding Dose - Response Relationships

Importance of Racemates and Active Metabolites in Understanding Dose - Response Relationships. James D. Coyle, Pharm.D. Winter, 2002. Dose – Effect Relationship for Most Drugs. Plasma concentrations and airway response resulting from 0.75 mg terbutaline, a beta-2 agonist, SQ.

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Importance of Racemates and Active Metabolites in Understanding Dose - Response Relationships

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  1. Importance of Racemates and Active Metabolites in Understanding Dose - Response Relationships James D. Coyle, Pharm.D. Winter, 2002

  2. Dose – Effect Relationship for Most Drugs

  3. Plasma concentrations and airway response resulting from 0.75 mg terbutaline, a beta-2 agonist, SQ

  4. Sources of Dose-Response Relationship Variability Body size Body composition Gender Diet Age Genetics Dose  Response Drug interactions Environment Pregnancy Disease Circadian rhythms Liver function Kidney function CV function

  5. Sources of Apparent Variability • Active metabolites • Administration of racemic mixtures

  6. Case 1: Need for Dosage Adjustmentin Patients with Kidney Impairment? • 2nd generation sulfonylureas (hypoglycemic agents) • Glyburide (Diaeta, Micronase) • Glipizide (Glucotrol) • Both extensively metabolized Glyburide: 3% excreted as unchanged drug in urine Glipizide: <5% excreted as unchanged drug in urine • Does the dose of these drugs need to be altered in patients with kidney impairment?

  7. Case 1 Continued • Drug Information Handbook • Glyburide: use not recommended in patients with CrCl < 50 mL/min • Glipizide: some investigators recommend not using if CrCl < 10 mL/min • Why are the recommendations so different when the fraction eliminated renally is so similar?

  8. Case 1 Continued • Hypothesis: glyburide has active metabolite that accumulates in renally-impaired patients while glipizide does not. • Glyburide has (less potent) active metabolite that is renally eliminated • Glipizide has (less potent) active metabolite that is renally eliminated • Why are dosing recommendations different?

  9. Case 1 Continued • Rationale • Approximately 36% of a glyburide dose is metabolized to its active metabolite • Only 2% of a glipizide dose is metabolized to its active metabolite

  10. Case 1 Continued • Conclusion Glyburide should not be used in patients with CrCl < 50 mL/min due to the accumulation of a major active metabolite, with resulting increase in hypoglycemic episodes. Glipizide may be used at usual doses, at least until CrCl < 10 mL/min.

  11. Case 2: Absence of concentration – response relationship for albuterol • Albuterol (Proventil, Ventolin): 2 agonist, bronchodilator • Many reports suggest • Plasma concentration highly variable (15-fold) after both oral doses and inhalation • Plasma concentration of albuterol not correlated with response • Conclusion: no relationship between albuterol plasma concentration and response?

  12. Albuterol *

  13. Case 2 Continued • Albuterol is racemic mixture of two enantiomers, (R)-albuterol (levalbuterol) and (S)-albuterol • R enantiomer has 100 X affinity for 2 receptor • S enantiomer assumed to be inactive, benign. May: oppose bronchodilatory effects have proinflammatory effects increase airway reactivity

  14. Concentration vs. time for R- (lower curve) and S- (upper curve) albuterol following single 2.50 mg nebulized dose of racemate.

  15. Case 2 Continued • Study of effects of levalbuterol vs. racemate (J Allergy Clin Immunol 1998;102:943-952. • Patients with asthma (n=328) • Randomized to receive (by nebulization) • 0.63 mg levalbuterol TID x 4 weeks • 1.25 mg levalbuterol TID x 4 weeks • 1.25 mg racemic albuterol TID x 4 weeks • 2.50 mg racemic albuterol TID x 4 weeks • Placebo • Outcome: FEV1 • Expectations?

  16. Case 2 Continued • Results • 0.63 mg levalbuterol = 2.50 mg racemic albuterol • TI for levalbuterol substantially greater Levalbuterol 0.63 mg

  17. Case 2 continued • Conclusions • Greater effect can be achieved by administering levalbuterol alone than with same levalbuterol dose administered as racemate • Adverse effects can be decreased by administering levalbuterol rather than racemate

  18. Case 3: Different Labetalol Concentration-Response Curves in Women than Men? • Labetalol HCl (Normodyne): nonselective -blocker and 1-blocker for oral and IV use in treatment of hypertension • Nearly completely absorbed, oral bioavailability of 30%, 50% bound to plasma protein, extensive conjugative and oxidative metabolism, <5% eliminated as unchanged drug in urine

  19. Case 3 continued • Study of labetalol kinetics and dynamics in men vs. women (Pharmacotherapy 2000;20:622-628). • Hypertensive patients (untreated DBP >95 but <115 mmHg) (n=19) • Treated with labetalol 100 mg BID, titrated up to maximum of 800 mg BID to achieve DBP < 90 mmHg • Primary outcome: 24 hour ABP • Plasma concentration vs. time profile also assessed at steady-state

  20. Case 3 continued

  21. Mean labetalol plasma concentrations at steady-state

  22. Labetalol BP response in men (right of pair) and women (left of pair)

  23. Case 3 continued • What’s going on here? • Concentrations are 80% higher in women • Same BP response Is the concentration – response relationship for labetolol different in women compared to men?

  24. Case 3 continued * * Labetalol HCl

  25. Case 3 continued • Labetalol is marketed as mixture of four isomers • R,R: most of -blocking activity which is largely responsible for antihypertensive effects • S,R: most of 1-blocking effects • R,S and S,S: relatively inactive

  26. Mean dose-corrected AUCs for labetolol stererisomers in women and men

  27. Case 3 Conclusions • Labetalol dose – response relationship same in men and women • SS concentrations of (R,R)-labetalol same in men and women • (R,R)-labetalol concentration – response relationship same in men and women • Higher labetalol concentrations in women due to inactive and 1-blocking isomers • Apparent difference in labetolol concentration – response relationship between men and women due to measurement of all isomers

  28. Conclusions • Presence of active metabolites or isomers may complicate understanding the dose-response relationship of drugs • Importance depends on activities of the compounds and their pharmacokinetic and dynamic properties • Administration of a drug that undergoes metabolism to an active metabolite or administration of a racemic mixture should be viewed as the simultaneous administration of two (or more) drugs until this factor has been shown to be clinically unimportant

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